Characterization of the GPR139 Receptor as a Potential Target for Obesity Treatment

• Grant number: 23/00848-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): August 01, 2024
• Effective date (End): July 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Licio Augusto Velloso
• Grantee: Ester dos Santos Alves
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID
• Associated scholarship(s): 24/14339-4 - Exploring Hipothalamic GPR139 Signal Transduction Pathways For Novel Obesity Therapeutics, BE.EP.DR

Abstract

Obesity is defined as the abnormal or excessive accumulation of fat that is epidemiologically associated with a number of other medical conditions that offer health risks as well as economic losses to the individual and to society. It is one of the most prevalent diseases on the planet. It results from an imbalance between energy expenditure and food intake, being, from the intuitive point of view, a problem of simple resolution. However, in practice, patients who develop obesity encounter enormous difficulties in reversing the condition or even in containing the progression of the disease. The pathophysiology of obesity results from both environmental and genetic factors. Genetic factors include mutations in genes encoding leptin, the leptin receptor, the melanocortin-4 receptor (MC4R), and the prohormone convertase enzyme involved in proopiomelanocortin (POMC) processing. The prevalence of obesity continues to grow, such that the search for new targets for prevention and treatment of obesity remains the focus of science. In this framework, G protein-coupled receptors (GPCRs) emerge as potential targets that have been studied in the context of obesity. An orphan GPCR is a receptor for which an endogenous ligand has not yet been identified. There are currently 121 non-sensory orphan GPCRs, including GPR139, which was first identified in 2005 as a member of the rhodopsin (class A) GPCR class. Previous studies have shown that GPR139 expression is restricted to the nervous system, particularly the striatum, thalamus, pituitary, habenula, and hypothalamus. Interestingly, the highest expression of GPR139 receptors was reported in the habenula, a region of the brain that has been shown to be critically involved in addiction, anxiety, and mood regulation. In a recent study, evidence was provided that TAK-041 is a potent and selective agonist of GPR139, which crosses the blood-brain barrier. Thus, the justification for this project is based on the lack of therapeutic targets for obesity and, considering that in the past, experimental studies were efficient in promoting advances in the area, identifying the GLP1 receptor as a target that today is a reality in the treatment of the disease, we believe that experimental studies can contribute to new advances in the area. The objective of this proposal is based on recent studies that identified GPR139 as a receptor expressed in the hypothalamus, responsive to nutritional interventions and involved in the control of energy balance in the body, and is focused on investigating and evaluating the impact of pharmacological activation of GPR139 on energy balance in mice.